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207

Failure of the lymphatic system to transport lymph from the

interstitial space back to the bloodstream results in lymphatic

stasis. If the collateral lymphatic circulation is insufficient and

all compensatory mechanisms are exhausted, the protein-rich

interstitial fluid accumulates and lymphedema develops. In

lymphedema, caused by either congenital or acquired dys-

function of the lymphatic system, the microcirculation in the

affected area of the body is disrupted. The transport of the

excess tissue fluid containing lymphocytes, different plasma

proteins, immunoglobulins, and cytokines is impaired

and chronic inflammatory changes in the subcutaneous tis-

sue and skin develop. Progress in ultrastructural, cytochemi-

cal, and imaging studies and improvement in conservative

and surgical treatment of lymphedema have stimulated

substantial interest in lymphatic disease.

Historical background

Lymph vessels were mentioned more than 2000 years ago by

Aristotle, who described nerves which contain colorless

liquids and later by members of the Alexandrian School of

Medicine, who recognized arteries in the mesentery full of

milk. This knowledge, however, was lost during the Middle

Ages, and it was only in the Renaissance that attention was fo-

cused again on the lymphatic system. The thoracic duct was

observed in 1563 by Eustachius, who called it vena alba

thoracis. He failed, however, to recognize the function of the

thoracic duct and its relation to the lymphatic system. The

discovery of the lymphatics is attributed to the Italian

anatomist Gasparo Aselli, who in 1622 observed the mesen-teric lymphatics in a well-fed dog. He also recognized the

function of the lacteals, although he suggested mistakenly that

the chyle absorbed from the intestine by the mesenteric lym-

phatics was transported to the liver. In 1651, Pecquet described

the thoracic duct and recognized the correct route of lym-

phatic transport from the mesenteric lymphatics through the

receptaculum chyli and the thoracic duct to the subclavian

vein. Further details on the anatomy of the lymphatic system

were published in the 17th century by Bartholin and Rudbeck,

and by the great anatomists of the 18th century, Mascagni and

Cruikshank. It was most likely William Hunter who recog-

nized the lymphatics as a separate system responsible for

absorption.

Although Hunter suggested that the lymphatics were

closed tubes, one of his students, Hewson, recognized that

they had physiologic orifices, which, like capillary tubes

sucked up tissue fluid. It was not until the turn of the 20th

century, however, that Starling confirmed the relationship

between the oncotic pressure of the plasma proteins and the

hydrostatic pressure in the capillaries.1,2 Starling suggested

that lymph formed by filtration of the blood through the capil-

lary walls. Drinker,3 and later Rusznyk and colleagues,4 de-

serve the credit for clarifying the details of protein absorption

from the intercellular space via the lymphatic system. Interest

in lymphatic diseases was greatly enhanced by Kinmonth,

who described a clinically usable technique of direct contrastlymphangiography in 1952.5 Improvement in other imaging

techniques, such as lymphoscintigraphy,6,7 indirect lymphan-

giography,8,9 and magnetic resonance imaging,1012 furthered

the understanding of the structure and function of the lym-

phatic system in different lymphatic disorders. Progress in

conservative management13,14 and development of micro-

surgical operations on the lymph vessels1517 also have stimu-

lated experimental and clinical research in lymphatic diseases.

Development of the lymphatic system

The lymphatic system is first apparent in the human fetus at 6weeks of gestation, and it consists of paired jugular, iliac, and

retroperitoneal lymph sacs (Fig. 18.1).18 The origin of the lym-

phatic system is controversial, but it is most likely a derivative

from the venous system. Another possible theory is that it

develops independently of the veins from the mesenchymal

tissue. The lymph vessels grow from the paired primitive

lymphatic sacs and coalesce along the major veins to form the

afferent vessels, nodes, and efferent lymphatic ducts. The

Physiologic changes in lymphaticdysfunction

Peter Gloviczki

18

Vascular Surgery: Basic Science and Clinical Correlations, Second EditionEdited by Rodney A. White, Larry H. Hollier

Copyright 2005 Blackwell Publishing


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cisterna chyli develops from one of the large retroperitoneal

lymph sacs, whereas the other forms the mesenteric lymphat-

ic system. There are paired thoracic ducts in the embryo, and

the mature thoracic duct develops from fusion of the upper

portion of the left and the lower portion of the right thoracic

duct. The right cervical lymphatic duct is formed by the right

jugular lymphatic sac. This receives lymph from the right face,

neck, and the right upper extremity, and from the upper part of

the right thorax and mediastinum. Abnormalities in the devel-

opment of the lymphatic system include agenesis, hypoplasia,

or hyperplasia of the lymphatics with valvular incompetence.

They may result in lymphedema or in abnormalities in the

circulation of the chyle, such as chylous ascites, chylothorax,

reflux of chyle to the pelvis or lower extremities, or protein-

losing enteropathy. Persistence of some of the embryonic

sacs may cause the development of lymphatic cysts, whichmay or may not communicate with the lymphatic system.

Anatomy of the lymphatic system

The adult lymphatic system consists of peripheral lymph ves-

sel, lymph nodes, and major lymphatic trunks. The peripheral

lymph vessels collect lymph from the lymphatic capillaries,

which absorb a portion of the interstitial fluid from the inter-

stitial space. Afferent lymph channels transport lymph to the

lymph-conducting elements of the lymph nodes, which filter

and further conduct the lymph fluid to efferent lymphatic

channels. Significant communications between the lymphatic

and venous system in lymph nodes normally do not exist.

Eighty percent of the lower extremity lymph is carried by

the superficial lymphatic system. Although there is a lateral

superficial bundle located around the lesser saphenous vein,

most of the lower extremity lymph is transported by lymph

channels of the superficial medial bundle (Fig. 18.2). There is a

deep lymphatic network that runs in close proximity to the

tibial and peroneal vessels and transports lymph through

the popliteal lymph nodes into the deep femoral lymphatics.

The superficial and the deep lymphatics join in the inguinal

lymph nodes and drain lymph toward the aortoiliac lym-

phatic system. The cisterna chyli is located between the aortaand the inferior vena cava, usually at the level of L1 to L2.

Mesenteric lymphatics join the lower extremity and pelvic

lymphatics at this level and drain through the thoracic duct to

the left subclavian vein (Fig. 18.3). A very small amount of

mesenteric lymph is drained toward the liver around the he-

patic vein and the diaphragm to the mediastinal lymphatics.

The upper extremity lymphatics run along the major veins

of the arm. Although the medial arm bundle is the most signif-

icant route of lymph drainage in normal patients, after axillary

node dissection lymph is drained primarily through the

lateral lymphatic bundle to the deltoideopectoral and supra-

clavicular nodes (Fig. 18.4).

Asingle layer of endothelial cells forms the inner layer of thelymphatic capillaries. Basal membranes similar to blood capil-

laries are not present. The lymphatic capillaries contain

bicuspid lymphatic valves, which play a crucial role in the

initial lymphatic transport and are responsible for the unidi-

rectional lymphatic flow. The capillaries are anchored by small

microfibrils that expand the endothelial cells and increase the

lumen of the capillaries if the tissue pressure is elevated.19,20

Although smaller molecules may traverse the lymphatic

PART I Vascular pathology and physiology

208

A

B C

Figure 18.1 Development of the lymphatic system. (A) Seven-week embryo

with paired iliac, retroperitoneal, and jugular lymph sacs. (B) At 9 weeks of

gestation, paired thoracic ducts are present with numerous connections

across the midline. (C) Portions of both primitive thoracic ducts persist to

form the thoracic duct in the adult. The right lymphatic duct is formed from

the primitive right jugular lymphatic sac. (From Cambria RA, Gloviczki P.

Lymphedema: pathophysiology and management. In: Callow AD, ed.

Vascular Surgery. Norwalk, CT: Appleton & Lange, 1995:1593.)


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CHAPTER 18 Physiologic changes in lymphatic dysfunction

209

endothelial cells with active phagocytosis, large molecules

enter through the gaps between the endothelial cells of the

lymphatic capillary.

Lymphatic physiology

According to Starlings law, hydrostatic and osmotic pressuresin the capillaries and in the interstitial space determine the

amount of interstitial fluid that is ultrafiltered from the blood

plasma. Additional factors responsible for interstitial fluid

exchange include capillary permeability, the number of active

capillaries, the ratio of precapillary arteriolar to postcapillary

venular resistance, and the total extracellular fluid volume.

The amount of fluid that moves across the capillary wall is

tremendous, considering that the cardiac output is about

8000 l during a 24-h period. It is likely that an amount equal to

the total plasma volume enters the interstitial place and leaves

through the venous end of the capillaries and the lymphatics

every minute.21 The lymphatic system is responsible for the

transport of 24 l of interstitial fluid daily. During the same

time, approximately 100g of plasma protein is carried back to

the circulation by the lymphatics.22 The protein content of the

lymph is somewhat less than that of the plasma, and lymph

vessels from various parts of the body contain different

amounts of protein (Table 18.1). The lymphatic capillaries are

able to transport large molecules, even those with a molecular

weight over 1kDa.23

Figure 18.2 Anatomy of major lymph vessels and lymph nodes of the lower

extremity. (From Gloviczki P. Microsurgical treatment for chronic

lymphedema: an unfulfilled promise? In: Bergan JJ, Yao JST, eds.

Venous Disorders. Philadelphia: WB Saunders, 1990:344.)

Figure 18.3 Anatomy of the thoracic duct.

(From Gloviczki P, Noel AA. Lymphatic

reconstructions. In: Rutherford RB, ed. Vascular

Surgery, 5th edn. Philadelphia: WB Saunders,

2000:2159, with permission from Elsevier.)


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The single most important determinant of lymph flowthrough the lymphatic capillaries and the collecting lymph

vessels is the intrinsic contractility of the lymph vessels. In

addition, lymph flow in influenced by increased interstitial

pressure, muscular activity, arterial pulsation, respiratory

pressure, and gravity. Increase in interstitial volume and inter-

stitial pressure results in opening of the gaps between the

endothelial cells of the terminal lymphatics and an increase in

lymphatic transport. Because the endothelial cells contain

actin and are able to contract actively, contraction of terminal

lymphatics with the help of competent valves enables rapid

lymphatic transport. Intrinsic contractility of the smooth

muscle in larger collecting vessels allows further propulsion of

the lymph. Strength and frequency of the contractions are

greatly influenced by changes in intraluminal pressure.24

Adrenergic stimulation25 and endothelin26 also have been

shown to result in contraction of the lymph vessels. Patentblue dye injected into the subcutaneous tissue is transported

centrally in the lymph vessels at the rate of 45mm/s, even

without any muscular exercise. Intrinsic contractions of the

lymph vessel wall with competent valves are able to propel

lymph intermittently against a pressure as high as 50 mmHg.

The major difference that distinguishes the lymphatic sys-

tem from the venous system is that the veins are filled with a

continuous liquid column. The lymphatic system, however, is

not fully primed, and only if there is longstanding stasis

does the lymph column fill the lymphatic channels complete-

ly.23 It is only in these conditions that muscular contraction or

external massage play an important role in forward propul-

sion of the lymph and facilitate lymphatic transport.

Pathophysiology of lymphedema

Lymphedema develops when the lymphatic load exceeds the

transport capacity of the lymphatic system. In patients with

lymphatic obstruction, numerous compensatory mechanisms

develop. These include collateral lymphatic circulation, de-

velopment of spontaneous lymphovenous anastomoses, and

increased activity of tissue macrophages to split macro-

molecules in the interstitial space, enabling them to be reab-

sorbed through the venous end of the capillaries (Fig. 18.5).If the lymphatic transport is impaired due to injury or ob-

struction to the lymph vessels and lymph nodes, the different

compensatory mechanisms can function effectively for a

period of time. This explains why chronic lymphedema of the

limbs may develop several months or even years after an

edema-free state after inguinal or axillary node dissection or

irradiation.

Lymphedema is a high-protein edema that, except very

early in the course of the disease, is nonpitting in nature (Fig.

18.6). Without treatment, the high-protein edema fluid in the

subcutaneous tissue will be replaced by fibrous material, in-

flammatory cells accumulate, and progressive fibrosis of the

subcutaneous tissue and skin develops. Fibrosis of the lymphvessels leads to loss of permeability and loss of intrinsic con-

tractility. Dilation of the lymph vessels causes valvular incom-

petence, and the inflammatory and fibrotic changes destroy

the valve leaflets, further decreasing the transport capacity of

the lymphatic system. Microsurgical reconstruction in this

late stage of lymphedema, using fibrotic and incompetent

lymphatics, cannot restore normal lymphatic transport.

Progression of lymphedema results in fibrotic obstruction of


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Table 18.1 Approxiamte protein content of lymph in humans*

Lymph origin Protein content (g/dl)

Ankle 0.5

Limbs 2

Intestine 4

Liver 6

Thoracic duct 4

*Data based on various studies in humans and animals.

(From Ganong WF. Review of Medical Physiology, 10th edn. Los

Altos, CA: Lange Medical Publications, 1981: 452.)

Figure 18.4 Anatomy of major lymph vessels and lymph nodes of the upper

extremity. (From Gloviczki P. Microsurgical treatment for chronic

lymphedema: an unfulfilled promise? In: Bergan JJ, Yao JST, eds.

Venous Disorders. Philadelphia: WB Saunders, 1990:344.)


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the lymph nodes and the major lymph vessels. Even the larger

lymphatic collaterals, which functioned effectively in the ini-

tial period after lymphatic obstruction, may occlude with

time. In this stage, dilated dermal lymphatics provide the only

lymphatic drainage of the extremity. Using noninvasive func-

tional tests, such as radionuclide lymphoscintigraphy per-

formed with technetium-labeled antimony sulfur colloid, it is

possible to repeat the studies in the same patient and docu-

ment progression of the disease (Fig. 18.7).

Lymphatic stasis also results in deficiency of important im-

munoglobulins, cytokines, and plasma proteins. Because of

chronic inflammatory changes in the subcutaneous tissue and

the skin, there frequently is increased vascularity in the lym-

phedematous limb, and inflammatory cells accumulate. Theaffected limb has an increased sensitivity to fungal and bacter-

ial infections. Obstructive lymphangitis further destroys the

lymphatic system and results in progression of the lymphede-

ma. In long-standing, neglected lymphedema, irreversible

sclerosis of the subcutaneous tissue and skin develops. Lym-

phangiosarcoma, which is a severe late complication of

secondary lymphedema, fortunately is rare.

Pathophysiology of chylous disorders

Disorders in the circulation of chyle usually are caused by lym-

phangiectasia or megalymphatics, with or without obstruc-tion of the thoracic duct (Fig. 18.8).27,28 Because of valvular

incompetence, chyle in these patients may reflux to the pelvis

or lower extremities, causing chylorrhea from small vesicles in

the skin of the limb, scrotum, or labia (Fig. 18.9). Reflux to the

kidney may lead to chyluria, whereas transudation through or

rupture of abdominal lymphatics results in chylous ascites.

Rupture of the lymphatics into the lumen of the gut causes

protein-losing enteropathy, and chylothorax develops if the


212

A

B

Figure 18.7 Lymphoscintigram in a 44-year-old woman with secondary

lymphedema of the right lower extremity. (A) Note absence of right iliac

nodes and the presence of right inguinal nodes and collaterals. (B) Note

deterioration of lymphatic drainage 10 months later. There is no filling of the

right inguinal nodes or collaterals. The patient had a recent episode of

lymphangitis.

Figure 18.8 Contrast lymphangiogram in an 18-year-old man with

lymphangiectasia, protein-losing enteropathy, and chylous ascites

demonstrates dilated and tortuous thoracic duct.


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thoracic duct or mediastinal, intercostal, or diaphragmatic

lymphatics rupture.Secondary chyloperitoneum or chylothorax is caused most

frequently by malignant tumors, primarily lymphoma, or by

injury to the thoracic duct. The latter usually is iatrogenic, oc-

curring during operations on the thoracoabdominal aorta2931

or, rarely, after a high translumbar aortography.32

Chyle is a sterile alkaline fluid, odorless, and milky in ap-

pearance. Its protein content is around 4g/dl and the fat con-

tent ranges from 0.4 to 4g/dl. The fat stains with Sudan stain

and this test confirms the diagnosis of chyle in the peritoneal or

thoracic aspirate. The specific gravity of chylous fluid isgreater than 1012g/dl.

Loss of chyle into the body cavities or through chylocuta-

neous fistulas has important physiologic consequences. If not

treated, it leads to malnutrition, hypoproteinemia, hypo-

cholesterolemia, hypocalcemia, immunodeficiency, and se-

vere metabolic disturbances.27,28 Lymphopenia and anemia

contribute to the poor immune function in these patients.

Chylous effusion in a patient with malignancy usually

CHAPTER 18 Physiologic changes in lymphatic dysfunction

213

A

B

Figure 18.9 (A) Chyle draining through small

vesicles of the skin at the left groin of a 16-year-

old girl with lymphangiectasia and severe reflux

of the chyle. (B) Intraoperative photograph of

dilated, incompetent iliac lymphatics

containing chyle.


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carries an ominous prognosis. The outcome of patients with

primary chylous disorders and reflux of the chyle depends on

the effectiveness of medical treatment. To compensate for the

physiologic changes caused by the loss of chyle, treatment is

directed at decreasing production of the chyle with a medium-

chain triglyceride diet, or by parenteral nutrition. In addition

to adequate calorie and protein replacement, calcium, lost in

chyle, also should be replaced. Reflux can be controlled effec-tively with radical excision and ligation of the retroperitoneal

lymphatics in most cases. In patients with chylous effusion,

the site of lymphatic rupture should be oversewn if medical

treatment, paracentesis, or thoracentesis are ineffective. In

some patients with protein-losing enteropathy, the most dis-

eased segment of the small bowel may have to be resected to

decrease loss of chyle into the gastrointestinal tract.27,28 Trans-

plantation of small bowel for severe mesenteric lymphangiec-

tasia remains a task of the future, and it requires, as do many

other aspects of lymphatic disorders, further clinical research.

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